The invention relates to the treatment and prevention of precancerous cell formation in the colon in those patients at risk for developing such precancerous cells. It also relates to preventing recurrence of such cell formation in those having been treated for cancer of the colon.
Cancer of the colon is a common and deadly disease in the Western world. Genetic predisposition plays an important role, but exposure to substances that initiate and promote cancer is essential for a malignant tumor to develop. Bile acids have been implicated as important cancer-promoting agents.
In the normal colon mucosa, epithelial cells line crypt along the mucosal wall. Those epithelial cells which line the colon exposed surface and approximately the upper ⅔ of the crypt are normally non-proliferating, while those lining the lower ⅓ of the crypts are proliferating. As the proliferating cells migrate toward the upper portion of the crypt they transform and lose their proliferative ability. Ultimately the oldest cells are shed from the colon surface in the normal functioning of the colon. However, when the proliferating epithelial cells are induced to retain their proliferative capacity after reaching the upper ⅓ of the crypt, the normal process may go awry and microadenomas form. The proliferating cell, now at the surface of the colon continues to proliferate and a polyp develops.
Polyps may be either benign or cancerous. Some never become cancerous, but it is believed that adenomatous polyps are the main precursors of colon cancer and that about 90% of colon cancers develop from adenomatous polyps. Most adenomas do not continue to grow in size, but those that do are more likely to develop malignant changes. Therefore, reducing the number of adenomas and/or preventing their growth substantially reduces the number of potential colon cancers in the future.
Since subjects once treated for colon cancer have a much greater risk for developing further adenomas and cancers, potential adenoma prevention is extremely valuable in this population. The same may be said for close blood relatives of those treated for colon cancer, who may be at increased risk for adenoma and colon cancer development.
Bile acids have been implicated as important cancer promoting agents. In the normal sequence of events, bile acids are conjugated with taurine and glycine, making them more hydrophilic. It is these conjugated bile acids that are primarily involved in the digestion of fat. The bulk of these are reabsorbed in the final segment of the small bowel. However some of the conjugated bile acids are not absorbed and pass further down the GI tract.
Bacterial modification of the conjugated bile acids occurs in the lower intestine or colon. Two primary pathways are involved, deconjugation and dehydroxylation. Free bile acids are produced from the conjugate and removal of the 7-alpha hydroxyl group results in formation of secondary bile acids. Each of these steps changes the bile acid to a more lipophilic compound and to one which is more cytotoxic and more cancer promoting than the unmodified compound.
Normal fecal bile acids in healthy adults have been reported as:
The normal healthy control is believed to have a proper balance of bile acids. If the lipophilic/hydrophilic balance of the bile acid pool is significantly upset in the lipophilic direction, the bile acids may become toxic or harmful to the colonic epithelial cells. It is believed that as the lipophilic nature of the bile acid pool increases, the mucosal epithelial cells are more likely to be damaged by the presence of the secondary bile acids, especially deoxycholate. The damaged cells then begin the repair process which includes inducing cell proliferation. Repeated and frequent damage repeatedly induces proliferation and repair. The process of apoptosis or programmed cell death may also be affected. Research in rats has shown that excessive lipophilic bile acids in the colon can impair apoptosis and possibly increase the risk of forming adenomas and cancer. In addition, once the cell membrane has been compromised, agents which would not affect or which would have a difficult time affecting the colonic mucosal epithelial cells are more likely to have a significant impact.
There is therefore a need for a method for the treatment and prevention of colorectal cancer.